Pantothenic acid is a water-soluble vitamin, also known as vitamin B5, which is a component of coenzyme A (CoA). Pantothenic acid is found in a large range of foods, such as fish, meat, eggs, milk products and vegetables, as a result of which natural deficiency is very rarely observed in humans. In the past studies have been carried out in which pantothenic acid deficiency has been induced experimentally in humans by administration of a pantothenic acid deficient diet (e.g. Fry et al. 1976, J. Nutr. Sci. Vitamology 22, 339-346) and/or a compound like omega-methyl pantothenic acid which is known to exhibit an anti-pantothenic acid-like effect (see e.g. Hodges et al. 1959, J. Clin. Invest. 38, 1421-1425). Symptoms exhibited by the participants of such trials were gastrointestinal complaints (nausea, vomiting, abdominal cramps), irritability, restlessness, fatigue, apathy, malaise, headache, insomnia, numbness or tingling of feet and hands, parasthesia, muscle cramps, staggering gait, hypoglycaemia and increased sensitivity to insulin (see e.g. Hodges et al. 1958, J. Clin. Invest. 37, 1642-1657; Report “Expert Group on Vitamins and Minerals 2003” published by the Food Standards Agency, Aviation House, 125 Kingsway, London WC2B 6NH, UK). In other studies, where humans were on a pantothenic acid free diet, no clinical signs of deficiency developed (Fry et al. 1976, J. Nutr. Sci. Vitminol. 22(4), 339-346. It is concluded that none of the above studies reveal that pantothenic acid deficiency is related to the loss of appetite or that pantothenic acid can be used to restore appetite loss. These studies neither reveal that pantothenic acid can be used to restore bodyweight. It is particularly noted that increased demands for pantothenic acid have never been associated with severe illnesses such as cancer, AIDS, catabolism as a result of respiratory diseases such as lung emphysema, severe traumata such as surgery and severe diarrhea such as for instance occurring with inflammatory bowel disease. In other words it is generally not believed that bad appetite and weight loss associated with any severe illness is caused by a pantothenic acid deficiency.
Vaughan and Vaughan (J. Nutrition, (1960) 70: 77-80) described the effect of cold on weight, food intake and acetylating acitivity of pantothenic acid deficient rats. They present some data from which it may derived that healthy rats, that are brought in a pantothenic acid-deficient state by feeding for 33 days an artificial diet that uses casein as protein source and vegetable oil as lipid source but which is devoid of pantothenic acid, benefit from the administration of pantothenic acid in terms of increase in weight and of food intake. The authors concluded however that there was no relation between level of pantothenic acid and food intake and that pantothenic acid does not have an influence on growth which is related to appetite. Moreover, no relation is made to a potential beneficial effect in human patients that have a completely different taste perception and especially no relation is made to human beings that suffer from terminal cancer, AIDS, COPD or other severe disorders.
EP 0914111 relates to methods and nutritional compositions for the prevention and treatment of cachexia and anorexia. In this document there is no suggestion of a beneficial effect of pantothenic acid to appetite, nor was indicated that the amount of saturated fatty acids, in particular myristic acid is of any relevance.
DE 4304394 concerns preparations for enteral feeding of oncologic patients to overcome problems related to weight loss. The preparations are characterised by a balanced composition of specific types of fats. Also preparations are disclosed that include calcium pantothenate and pantothenic acid but no relation between the level of pantothenic acid and stimulating appetite was mentioned or suggested.
Several documents such as DE 29916231, JP 5294833 and U.S. Pat. No. 6,322,821 describe multivitamin compositions including calcium pantothenate that are useful to treat amongst others loss of appetite in humans and cows. Neither of these documents however disclose a critical role for the level of pantothenic acid in the compositions.
No recommended dietary allowance (RDA) for pantothenic acid intake has been set by the Food and Nutrition Board of the Institute of Medicine (Eissenstat et al. 1986, Am. J. Clin. Nutr. 44(6), 931-937). Instead, only approximate adequate daily dietary intake values (AI) have been described for different age or target groups, ranging from 1.7 mg/day in infants to 4-5 mg/day in adults and 6-7 mg/day in pregnant or breastfeeding women (Department of Health, 1991, In: Dietary reference values for food, energy and nutrients for the United Kingdom. HMSO, London, p113-115). Also, no tolerable upper level for pantothenic acid has been set, as there seems to be no adverse effect of consumption of large amounts. The only reported adverse effect described is the occurrence of diarrhea, associated with intake of 10-20 mg calcium D-pantothenate per day (Flodin 1988, Pharmacology of micronutrients; New York, Alan R. Liss, Inc.). The UK Council for Responsible Nutrition has recommended an Upper Safe Level of pantothenic acid of 1000 mg/day for long and short term supplementation (leaflet CRN 1999, The safe use of supplements benefit good health).
Apart from dietary pantothenic acid uptake, bacteria colonising the colon are also able to produce pantothenic acid, and it is therefore feasible that the pantothenic acid produced in the subject's intestine is adsorbed and provides a further source of this vitamin (Said et al. 1998, Am. J. Physiol. 275:C1365-1371). However, it is not known whether internally produced pantothenate contributes in significant amounts to the body's overall pantothenate levels. In experimental set-ups, the internal bacterial production of pantothenic acid often necessitates treatment with antibiotics in order to elicit pantothenic acid deficiency in test animals (Stein and Diamond 1989, J. Nutr. 119(12), 1973-1983).
Commercially available vitamin supplements mostly also contain pantothenic acid, or derivatives thereof, such as calcium pantothenate, sodium pantothenate or panthenol, which are more stable than pantothenic acid. Mostly the D-isomer is used, although DL-raceniic mixtures may also be used. Pantothenate, which is taken up with the diet, is adsorbed in the intestine and transported via the blood (primarily as bound forms within erythrocytes) to various body tissues. The majority of tissues import pantothenic acid from the blood via an active sodium-dependent co-transport mechanism. Blood plasma levels of pantothenic acid have not been found to correlate well with dietary intake levels, while a good correlation between urinary excretion of pantothenate and dietary intake has been found (Eissenstat et al. 1986, American J. of Clinical Nutrition 44, 931-937).
Dietary pantothenic acid supplements have been proposed to have a beneficial effect in the treatment of obesity. Leung 1995, Medical Hypotheses 44, 403-405) describes that, when the intake of a low calorie containing diet (about 1000 calories/day) is supplemented by co-administration of large daily amounts of pantothenic acid (about 10 g/day), a gradual weight loss of about 1 kg per week is achieved while dieters do not feel hunger or weakness and ketone body formation is significantly reduced (only detectable in trace amounts in the urine). In particular, it is suggested that pantothenic acid may be called a ‘hunger suppressant’ when taken at a large dose during periods of low calorie intake.
This disclosure does, however, not suggest any other uses for pantothenic acid than the supplementation of low calorie diets in order to solve the problem of hunger, weakness and ketone body formation associated with dieting. Further, it clearly teaches the use of pantothenic acid as a hunger suppressant. In contrast hereto, the present inventors found that the administration of compositions comprising pantothenic acid, or equivalents thereof, to subjects suffering from lost appetite, especially lack of appetite resulting from diseases or disease therapies, stimulates appetite or hunger and increases body weight and muscle mass in (specific groups of) humans.
Myristic acid is a saturated fatty acid, like for example lauric acid, palmitic acid and stearic acid which occurs in a few vegetable oils like coconut oil. In small quantities it therefore may be present in artificial clinical nutrition. Saturated fatty acids are considered as an undesirable lipid component which may cause cardiovascular problems. Saturated fatty acids and coconut oil are difficult to use in the manufacture of liquid formulas because they can cause excessive creaming and therefore inclusion thereof is avoided in the state of the art. Instead corn oil, rapeseed oil, sunflower or soybean oil are included which form homogeneous emulsions in complete formulae and comprise <0.5% myristic acid. These also comprise high amounts of linoleic acid which is considered highly desirable.